We propose to assess the impact of sex-steroid hormones and prostate cancer (PCa) progression in the context of the recently identified TMPRSS2:ERG translocation, a novel gene fusion of the 5'-untranslated region of the androgen-regulated TMPRSS2 promoter and the ETS transcription factor family member. The TMPRSS2:ERG translocation is a common molecular event in PCa, and emerging data (including our own) suggest men with tumors with the translocation tend to have a worse cancer prognosis. The regulation of TMPRSS2 by androgens and possibly estrogens is intriguing and illuminates a potential mechanism whereby sex hormones could drive tumor growth and proliferation leading to worse cancer survival. We have identified 1,500 men diagnosed with incident PCa in the Physicians' Health Study and Health Professionals Follow-up Study during 1982 to 2006, and will continue prospective follow-up through 2012 for outcomes (175 will have developed metastatic or fatal disease). We have assembled a repository of archival tumor tissue, and will characterize the TMPRSS2:ERG tumor status using fluorescent in situ hybridization. We will explore the role of the TMPRSS2:ERG fusion on PCa progression. Moreover, we will examine whether circulating levels of sex hormones or variation in genes involved in sex hormone signaling or metabolism interact with the fusion to affect progression; we hypothesize that men with fusion positive tumors have a worse prognosis if they are exposed to high sex hormone levels. We will evaluate whether obesity, with its known regulation of the hormonal milieu causing higher levels of estrogen and reduced testosterone, is associated with PCa progression by interacting with the TMPRSS2:ERG fusion. At the tumor level, we will examine the relation between fusion status, alone and in concert with hormones, and extent of tumor angiogenesis, cellular proliferation and apoptosis. Finally, we will evaluate whether men with fusion positive tumors have a more favorable response to androgen deprivation therapy compared to those without the TMPRSS2:ERG fusion. Based on the incidence of PCa in the United States and frequency of the fusion, more than 100,000 men diagnosed each year have a fusion positive PCa. If these tumors are indeed more aggressive, this number reflects a considerable burden of men at risk of progression. As such, an understanding of the TMPRSS2:ERG fusion on PCa survival in light of the hormonal milieu could have significant public health impact, and illuminate opportunities for primary and secondary prevention or improved patient selection for specific therapeutic intervention.